SUMMARY The goal of this proposed research is to advance our understanding of the hepatic lymphatic system with focus on two key areas: the mechanism of hepatic lymphangiogenesis and the role of lymphatic vessels in liver pathophysiology. The lack of experimental models has limited progress on this topic. In this regard, our preliminary data demonstrate that partial portal vein ligation (PPVL) in the rat, a simple surgical model of portal hypertension, provides an excellent model to study the hepatic lymphatic vasculature. Using the PPVL model, we will first determine the mechanism of hepatic lymphangiogenesis. Our preliminary study has provided 3 key findings: 1) hepatic sympathetic nerves are the major sources of vascular endothelial growth factor C (VEGF-C), the potent inducer of lymphangiogenesis, 2) macrophages are not the sources of VEGF-C, but still contribute to hepatic lymphangiogenesis possibly via synthesis of fibronectin1, essential for VEGF-C/VEGFR3 signaling, and 3) hepatic sympathetic nerves facilitate macrophage recruitment to the portal tract. We thus hypothesize that sympathetic nerves play a central role in hepatic lymphangiogenesis as a source of VEGF-C and by facilitating macrophage recruitment. Second, we will examine the significance of lymphangiogenesis for liver pathophysiology. One of the functions of lymphatic vessels is to collect infiltrating immune cells. We thus hypothesize that lymphangiogenesis helps to decrease inflammation and inhibiting lymphangiogenesis should increase inflammation, thereby promoting disease progression. To test these hypotheses, we propose to examine the following three specific aims: Aim 1 Determine the mechanism by which sympathetic nerves regulate hepatic lymphangiogenesis. Aim 2 Determine the mechanism by which Kupffer cells/macrophages promote hepatic lymphangiogenesis. Aim 3 Determine the role of lymphangiogenesis in the development of liver fibrosis.